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J. Biol. Chem., Vol. 281, Issue 26, 17909-17919, June 30, 2006

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Identification of Ligands with Bicyclic Scaffolds Provides Insights into Mechanisms of Estrogen Receptor Subtype Selectivity^*

Robert W. Hsieh^¶1, Shyamala S. Rajan, Sanjay K. Sharma, Yuee Guo, Eugene R. DeSombre, Milan Mrksich^¶2, and Geoffrey L. Greene³

From the Ben May Institute for Cancer Research, the Department of Biochemistry and Molecular Biology, and the ^¶Howard Hughes Medical Institute and Department of Chemistry, University of Chicago, Chicago, Illinois 60637

Estrogen receptors (ER) and (ER) have distinct functions and differential expression in certain tissues. These differences have stimulated the search for subtype-selective ligands. Therapeutically, such ligands offer the potential to target specific tissues or pathways regulated by one receptor subtype without affecting the other. As reagents, they can be utilized to probe the physiological functions of the ER subtypes to provide information complementary to that obtained from knock-out animals. A fluorescence resonance energy transfer-based assay was used to screen a 10,000-compound chemical library for ER agonists. From the screen, we identified a family of ER-selective agonists whose members contain bulky oxabicyclic scaffolds in place of the planar scaffolds common to most ER ligands. These agonists are 10–50-fold selective for ER in competitive binding assays and up to 60-fold selective in transactivation assays. The weak uterotrophic activity of these ligands in immature rats and their ability to stimulate expression of an ER regulated gene in human U2OS osteosarcoma cells provides more physiological evidence of their ER-selective nature. To provide insight into the molecular mechanisms of their activity and selectivity, we determined the crystal structures of the ER ligand-binding domain (LBD) and a peptide from the glucocorticoid receptor-interacting protein 1 (GRIP1) coactivator complexed with the ligands OBCP-3M, OBCP-2M, and OBCP-1M. These structures illustrate how the bicyclic scaffolds of these ligands are accommodated in the flexible ligand-binding pocket of ER. A comparison of these structures with existing ER structures suggests that the ER selectivity of OBCP ligands can be attributed to a combination of their interactions with Met-336 in ER and Met-421 in ER. These bicyclic ligands show promise as lead compounds that can target ER. In addition, our understanding of the molecular determinants of their subtype selectivity provides a useful starting point for developing other ER modulators belonging to this relatively new structural class.

Received for publication, December 22, 2005 , and in revised form, April 28, 2006.

^* This work was supported by the Ludwig Fund for Cancer Research; NCI, National Institutes of Health, Grant CA89489; and Department of Defense Grant W81XWH-04-1-0791. Use of the Argonne National Laboratory Structural Biology Center and BioCARS beamlines at the Advanced Photon Source was supported by the United States Department of Energy, Office of Energy Research, under Contract W-31-109-ENG-38. Use of the BioCARS Sector 14 was also supported by the National Institutes of Health, National Center for Research Resources, under Grant RR07707. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

The atomic coordinates and structure factors (code 1ZKY, 2FAI, and 2B1V) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

¹ Supported by the University of Chicago unendowed Medical Scientist Training Program.

² To whom correspondence may be addressed: Dept. of Chemistry and Howard Hughes Medical Institute, University of Chicago, 929 E. 57th St., Chicago, IL 60637. Tel.: 773-702-1651; Fax: 773-702-1677; E-mail: mmrksich{at}uchicago.edu. ³ To whom correspondence may be addressed: Ben May Institute for Cancer Research, University of Chicago, W330, 929 E. 57th St., Chicago, IL 60637. Tel.: 773-702-6964; Fax: 773-834-9029; E-mail: ggreene{at}uchicago.edu.

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